The candidate is a board-certified internist specializing in lipidology, starting a career in translational research focused on lipoprotein metabolism, its pathophysiology, and treatment. His short-term goal is mentored support to complete essential formal and practical training supporting his long-term goal, to develop into an independent academic investigator performing high-quality mechanistically-oriented patient-oriented research advancing lipid science and atherosclerosis prevention. Key skills are directed at probing mechanisms, including the use of pharmacologic and physiologic challenges and molecular techniques. The candidate will gain a working knowledge of the proper application of these skills and a publication record in their use, helping him to compete as an independent researcher. This training will enhance the clinical trials of the research project, and include two provocative nutrient challenges, pharmacodynamic modeling, and mRNA expression of clinical samples using in situ hybridization and RT-PCR. Specific hypotheses related to Niacin's Effects on Fatty Acids and Inflammatory Markers (NEFA-IM) are assessed using a niacin challenge to provoke acute changes in insulin sensitivity and postprandial lipidemia. The overall hypothesis is that free fatty acid rebound following niacin a) mediates niacin-induced insulin resistance, and b) interferes with postprandial triglyceride lowering and HDL raising. Hypotheses are tested .by suppressing the free fatty acid rebound with a prostaglandin synthesis inhibitor. Two clinical trials evaluate subjects with metabolic syndrome, a) during an intravenous glucose challenge, and b) an oral fat tolerance test. Complementary analyses include ex vivo analyses from clinical samples evaluated with molecular techniques, in collaboration with appropriate specialists. Advisors are established researchers with expertise related to the major aims, and a history of successful mentorship in an environment known for its emphasis on translational medicine of the kind proposed. This award will help the candidate develop needed skills and preliminary data to support an application for traditional funding that would translate promising findings into the clinical therapy setting. RELEVANCE (See instructions): Niacin is effective at treating high cholesterol and preventing heart attacks, but sometimes raises blood sugar. The purpose of this study is to test a technique that may prevent changes in sugar and even improve cholesterol lowering by niacin. If this is successful, it may lead to future strategies to improve niacin therapy. (End of Abstract)